(19)
(11) EP 0 247 266 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication:
02.12.1987 Bulletin 1987/49

(21) Application number: 86310011.1

(22) Date of filing: 22.12.1986
(51) International Patent Classification (IPC)4C07D 451/04, C07D 451/12, C07D 451/14, C07D 453/02, C07D 209/08, A61K 31/46, A61K 31/445
(84) Designated Contracting States:
BE CH DE ES FR GB GR IT LI LU NL SE

(30) Priority: 07.01.1986 GB 8600262
07.11.1986 GB 8626632

(71) Applicant: BEECHAM GROUP PLC
Brentford, Middlesex TW8 9BD (GB)

(72) Inventors:
  • King, Francis David Beecham Pharmaceuticals
    The Pinnacles Harlow Essex, CM19 5AD (GB)
  • Joiner, Karen Anne Beecham Pharmaceuticals
    The Pinnacles Harlow Essex, CM19 5AD (GB)

(74) Representative: Tocher, Pauline et al
SmithKline Beecham plc Corporate Intellectual Property SB House Great West Road
Brentford, Middlesex TW8 9BD
Brentford, Middlesex TW8 9BD (GB)


(56) References cited: : 
   
       


    (54) Indole derivatives having an azabicyclic side chain, process for their preparation, intermediates, and pharmaceutical compositions


    (57) Compounds of formula (I), and pharmaceutically acceptable salts thereof:

    wherein

    L is NH or O;

    X and Y are independently selected from hydrogen or C1-4alkyl, or together are a bond;

    R1 and R2 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl-C1-4 alkyl, or together are C2-4 polymethylene;

    R3 and R4 are independently selected from hydrogen, halogen, CF3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, Ci-7 acyl, Ci-7 acylamino, C1-6 alkylsulphonylamino, N-(C1-6 alkylsul- phonyl)-N-C1-4 alkylamino, C1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C1-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl Ci-4 alkyl, phenyl or phenyl C1-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene;

    Z is a group of formula (a), (b) or (c)





    wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and

    R5 or R6 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1- 2 alkyl or C2-7 alkenyl-C1-4 alkyl; having 5-HT M-receptor antagonist activity, a process for their preparation and their use as pharmaceuticals.




    Description


    [0001] This invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions containing them, to a process and intermediates for their preparation, and to their use as pharmaceuticals.

    [0002] GB 2100259A and 2125398A, and EP-A-158265 describe benzoates and benzamides having an azabicyclic siae chain and possessing 5-HT antagonist activity.

    [0003] A class of novel, structurally distinct compounds has now peen discovered. These compounds have 5-HT M-receptor antagonist activity, anti-emetic activity and/or gastric motility enhancing activity.

    [0004] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

    wherein

    L is NH or O;

    X and Y are independently selected from nydrogen or Cl-4 alkyl, or together are a bond;

    R1 and R2 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl-Cl-4 alkyl, or together are C2-4 polymethylene;

    R3 and R4 are independently selected from hydrogen, halogen, CF3, Cl-6 alkyl, Cl-6 alkoxy, Cl-6 alkylthio, Cl-7 acyl, C1-7 acylamino, Cl-6 alkylsulphonylamino, N-(Cl-6 alkylsulphonyl)-N-C1-4 alkylamino, C1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C1-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, phenyl or phenyl C1-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene;

    Z is a group of formula (a), (b) or (c)





    wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and

    R5 or R6 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-Cl-2 alkyl or C2-7 alkenyl-Cl-4 alkyl.

    Preferably L is NH.

    Suitable values for X and Y include hydrogen, methyl, ethyl, n- and iso-propyl; or together are a bond.

    Often X and Y are both hydrogen.



    [0005] Suitable values for R1 or R2 include hydrogen, methyl, ethyl, n- and iso-propyl; prop-2-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl and l-methylprop-2-yl in their E and Z forms where stereoisomerism exists; or Rl and R2 together are as defined in formula (I). Often Rl and R2 are both hydrogen.

    [0006] Values for R3 and/or R4 include hydrogen, fluoro, chloro, bromo, CF3, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, acetyl, propionyl, acetylamino, methylsulphonylamino, methylsulphinyl, hydroxy, nitro; and amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-methylamino any of which may be optionally substituted by one or two methyl groups or by a cyclopentyl or cyclohexyl group or disubstituted by C4 or C5 polymethylene; R3 is often hydrogen and R4 is hydrogen or a 4-substituent, such as halo or methoxy.

    [0007] Preferably n is 2 or 3 and p, q and r are 1 or 2.

    [0008] Examples of R5/R6 when Cl-7 alkyl include as groups of interest Cl-3 alkyl such-as methyl, ethyl and n- and iso-propyl. Within Cl-7 alkyl, C4-7 alkyl are also of interest, especially those of the formula (CH2)uRg wherein u is 1 or 2 and Rg is a secondary or tertiary C3-6 alkyl group. Examples of C4-7 alkyl include n-, sec- and tert-butyl, n-pentyl, n-heptyl, ana iso-butyl, 3-methylbutyl, and tert-butylmethyl.

    [0009] Examples of R5/R6 when C3-8 cycloalkyl-C1-2 alkyl include in particular those wherein the cycloalkyl moiety is cyclohexyl or cyclopropyl. Examples of include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, tert-butylmethyl, iso-propylmethyl, iso-propylethyl and tert-butylethyl.

    [0010] R5/R6 may in particular be cyclopropylmethyl, cyclohexylmethyl, iso-propylmethyl, tert-butylmethyl or iso-propylethyl, preferably tert-butylmethyl.

    [0011] Examples of R5/R6 when C2-7 alkenyl-C1-4 alkyl include prop-2-enyl, but-2-enyl, but-3-enyl, l-methylenepropyl and 1-methyl-prop-2-enyl in their E and Z forms when stereoisomerism exists.

    [0012] R5/R6 is preferably methyl or ethyl, most preferably methyl.

    [0013] The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, a-glyeerophosphoric, and glucose-l-phosphoric acids.

    [0014] The pharmaceutically acceptable salts of the compounds of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.

    [0015] Preferably the acid addition salt is the hydrochloride salt.

    [0016] Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R10-T wherein R10 is C1-6 alkyl, phenyl-Cl-6 alkyl or C5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R10 include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.

    [0017] The compounds of formula (I) may also form internal salts such as pharmaceutically acceptable N-oxides.

    [0018] The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.

    [0019] It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods.

    [0020] It will also be realised that compounds of formula (I) may adopt an endo or exo configuration with respect to L. The endo configuration is preferred.

    [0021] A group of compounds within formula (I) is of formula (II):

    wherein X1 ana Yi are independently hydrogen, methyl or ethyl, or together are a bond, R11 and R21 are independently hydrogen, methyl or ethyl and the remaining variables are as defined in formula (I).

    [0022] Examples of the variables and preferred variables are as so described for corresponding variables in relation to formula (I).

    [0023] A further group of compounds within formula (I) is of formula (III):

    wherein ql is 1 or 2 and the remaining variables are as defined in formulae (I) and (II).

    [0024] Examples of the variables and preferred variables are as so described for the corresponding variables in formula (I).

    [0025] There is a further group of compounds within formula (I) of formula (IV):

    wherein rl is 1 or 2 and the remaining variables are as defined in formulae (I) and (II).

    [0026] Examples of the variables and preferred variables are so described as the corresponding variables in formula (I).

    [0027] The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (V):

    with a compound of formula (VI):

    wherein

    [0028] G is COQ1, where Q1 is a leaving group, or hydrogen; and, when G is COQ1, J is NH2, or OH or a reactive derivative thereof or, when G is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-L-linkage with the compound of formula (V); Zl is Z as defined or wherein R5/R6 is replaced by a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting any R3 and R4 group to another R3 and R4 group respectively, converting Zl, when other tnan Z, to Z; converting X and Y to other X and Y; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

    [0029] Examples of leaving groups Ql, displaceable by a nucleophile, include halogen such as chloro and bromo; Cl-4 alkoxy, such as CH30 and C2H5O-; PhO-; activated hydrocarbyloxy, such as Cl5C6O- or C13CO-; succinimidyloxy; and imidazolyloxy. Preferably Q1 is halogen, most preferably chloro.

    [0030] If a group Ql is a halide or imidazolyloxy, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0-100°C, in particular 10-80°C are suitable.

    [0031] If a group Ql is Cl-4 alkoxy, phenoxy, activated hydrocarbyloxy or succinimidyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. In this instance, it is preferred that the group Q1 is C13CO- or succinimidyloxy and that the reaction is carried out in toluene at reflux temperature.

    [0032] When J is OH or a reactive derivative thereof, the reactive derivative is often a salt, such as the lithium, sodium or potassium salt.

    [0033] When G is hydrogen, J-Zl may be a compound of formula (VII) or (VIII) when L is NH; or of formula (IX) when L is O:





    wherein
    Zl is as hereinbefore defined, and Q2 and Q3 are leaving groups, preferably C13CO and Cl respectively.

    [0034] When J-Zl is of formula (VII), the reaction is preferably carried out in an inert solvent, under conventional conditions 0-100°C.

    [0035] Q2 is a leaving group as defined for Q1 hereinbefore; and the reaction is carried out in accordance with the conditions described herein for the reaction wherein G is COQ1.

    [0036] Examples of Q3, displaceable by a nucleophile, include halogen, such as chloro and bromo; and activated hydrocarbyloxy, such as Cl5C6O- and Cl3CO.

    [0037] If a group Q3 is a halide, the reaction is carried out as described above for Q1 halide.

    [0038] If Q3 is activated hydrocarbyloxy, the reaction is carried out as described for Q1 activated hydrocarbyloxy.

    [0039] It will be apparent that compounds of the formula (I) containing an R3 or R4 group which is convertible to another R3 or R4 group are useful novel intermediates. A number of such conversions is possible not only for the end compounds of formula (I), but also for their intermediates as follows:

    (i) a hydrogen substituent is convertible to a nitro substituent by nitration;

    (ii) a nitro substituent is convertible to an amino substituent by reduction;

    (iii) a C1-7 acylamino substituent is convertible to an amino substituent by deacylation;

    (iv) an amino substituent is convertible to a Cl-4 acylamino substituent by acylation with a carboxylic acid derivative;

    (v) a hydrogen substituent is convertible to a halogen substituent by halogenation;

    (vi) a Cl-6 alkylthio or C1-6 alkylsulphinyl substituent is convertible to a Cl-6 alkylsulphinyl or a C1-6. alkylsulphonyl substituent respectively by oxidation;

    (vii) an amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-N-Cl-4 alkylamino substituent is convertible to a corresponding substituent substituted by one or two groups selected from Cl-6 alkyl, C3-8 cycloalkyl, Cl-4 alkyl or phenyl Cl-4 alkyl groups any of which phenyl groups may be substituted by one or more groups selected from halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy and nitro, or disubstituted by C4-5 polymethylene, by N-alkylation;

    (viii) an amino substituent is convertible to a Cl-6 alkylsulphonylamino group or an aminosulphonylamino group optionally N-substituted as defined by acylation with a Cl-6 alkylsulphonyl chloride or di-substituted aminosulphonyl chloride.

    (ix) A Cl-4 alkylamino substituent group is convertible to a N-(C1-6 aikylsulphonyl)N-C1-4 alkylamino group or an N-(amino sulphonyl)N-C1-4 alkylamino group optionally N-substituted as defined by acylation with a Cl-6 alkylsulphonyl chloride or di-substituted aminosulphonyl chloride.



    [0040] Conversions (i) to (ix) are only exemplary and are not exhaustive of the possibilities.

    [0041] In regard to (i), nitration is carried out in accordance with known procedures.

    [0042] In regard to (ii), the reduction is carried out with a reagent suitable for reducing nitroanisole to aminoanisole.

    [0043] In regard to (iii), deacylation is carried out oy treatment with a base, such as an alkali metal hydroxide.

    [0044] In regard to (iv), (viii), and (ix) the acylation is carried out with an acylating agent, such as the corresponding acid or acid chloride. Formylation is carried out with the free acid.

    [0045] In regard to (v), halogenation is carried out with conventional halogenating agents.

    [0046] In regard to (vi), oxidation is carried out at below ambient temperatures in a non-aqueous solvent, such as a chlorinated hydrocarbon, in the presence of an organic peracid, such as 3-chloroperbenzoic acid, or in water in the presence of a soluble strong inorganic oxidant, such as an alkali metal permanganate or in aqueous hydrogen peroxide. It will be realised that this process may also N-oxidise the N- moiety of a side chain (a), (b) or (c) and suitable precautions will routinely be taken by those skilled in the art.

    [0047] In regard to (vii), alkylation is carried out with a corresponding alkylating agent such as the chloride or bromide under conventional conditions.

    [0048] Zl when other than Z may have a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups as defined for R3 and R4. Such oenzyl groups may, for example, be removed, when R3 or R4 is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (X):

    wherein Z2 is of formula (d) or (e)



    wherein the variables are as defined in formula (I).

    [0049] This invention also provides a further process for the preparation of a compound of the formula (I) which comprises N-alkylating a compound of formula (X), and optionally forming a pharmaceutically acceptable salt, of the resulting compound of the formula (I).

    [0050] In this further process of the invention 'N-alkylation' comprises the substitution of the N-atom depicted in formula (X) by any group R5/R6 as hereinbefore defined. This may be achieved by reaction of the compound of formula (X) with a compound R5Q4 or R6Q4 wherein R5 and R6 are as hereinbefore defined and Q4 is a leaving group.

    [0051] Suitable values for Q4 include groups displaced by nucleophiles such as Cl, Br, I, OS02CH3 or OS02C6H4pCH3.

    [0052] Favoured values for Q4 include Cl, Br and I.

    [0053] The reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slight above.

    [0054] Alternatively, 'N-alkylation' may be effected under conventional reductive alkylation conditions when the group R5 or R6 in the compound of formula (I) contains a methylene group adjacent to the N-atom in the bicycle.

    [0055] Interconverting R5 or R6 in the compound of the formula (X) before coupling with the compound of the formula (V) is also possible. Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C2-7 alkanoyl group, before R5/R6 interconversion.

    [0056] When R5 or R6 in the compound of formula (VI) contains a methylene group adjacent to the N-atom in the bicycle it is often convenient in the preparation of such a compound of formula (VI) to prepare the corresponding compound wherein the methylene group is replaced by -CO-, or for R5 or R6 is methyl, where the methyl group is replaced by esterified carboxyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (V).

    [0057] The compounds of formula (V) and (VII are known or are preparable analogously to, or routinely from, known compounds. Intermediates of formula (V) wherein G is H and X and Y are hydrogen may be prepared from the corresponding intermediate wherein X and Y are a bond. Intermediates of formula (V) wherein G is COQ1 form an aspect of the invention.

    [0058] Compounds of the formula (VI) wherein Z is of formula (c) may be prepared as described in European Patent Publication No. 115933 or by analogous methods thereto.

    [0059] Compounds of the formula (X) are novel and form an aspect of the invention.

    [0060] It will be realised that in the compound of the formula (I) the -CO-L-linkage may have an endo or exo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo and exo isomer may if desired be synthesised from the corresponding endo or exo form of the compound of the formula (VI).

    [0061] Compounds of the formula (I) wherein X and Y are both hydrogen may be converted to the corresponding compounds wherein X and Y are a bond by conventional oxidation, and this is the preferred method of preparation when X and Y are a bond. Compounds of the formula (I) wherein X and Y are a bond may be converted to the corresponding compounds wherein X and Y'are hydrogen by reduction; however it is preferred that this is carried out on the compound of formula (V) wherein G is H prior to coupling.

    [0062] Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.

    [0063] The compounds of the present invention are 5-HT antagonists and it is thus believed may generally be used in the treatment or prophylaxis of migraine, cluster headaches and trigeminal neuralgia. Compounds which are 5-HT antagonists may also be of potential use in the treatment of CNS disorders such as anxiety and psychosis; arrhythmia, obesity and irritable bowel syndrome.

    [0064] The compounds of the present invention also have anti-emetic activity; in particular that of preventing cytotoxic agent or radiation induced nausea and vomiting. Examples of cytotoxic agents include cisplatin, doxorubicin and cyclophosphamide.

    [0065] The compounds of the present invention also have gastric motility enhancing activity, useful in the treatment of disorders such as retarded gastric emptying, dyspepsia, flatulence, oesophagal reflux and peptic ulcer.

    [0066] The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

    [0067] Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.

    [0068] Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

    [0069] Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

    [0070] Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

    [0071] Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

    [0072] The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

    [0073] For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

    [0074] Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

    [0075] The invention further provides a method of treatment or prophylaxis of migraine, cluster headache, trigeminal neuralgia and/or emesis in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

    [0076] An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.1 to 50 mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.

    [0077] No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.

    [0078] The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.

    [0079] The following Examples illustrate the preparation of compounds of formula (I); the following descriptions illustrate the preparation of intermediates.

    [0080] N.B. Nomenclature is based on Chemical Abstracts Index Guide 1977 published by the American Chemical Society.

    Description 1


    1-(2,3-Dihydro)-indolyltrichloromethyl carbamate (Dl)



    [0081] 

    To 2,3-dihydroindole (5g) in dry dichloromethane (140ml) and triethylamine (5.85ml) at 0° was added dropwise trichloromethyl chloroformate (5ml) in dry dichloromethane (20ml). The reaction mixture was stirred at room temperature for 2h, then washed with water (5ml) and 5N hydrochloric acid solution (5ml). The organic phase was dried (Na2S04), the solvent evaporated in vacuo and the residue purified by filtration through a short alumina column, eluting with dichloromethane to give the title compound (Dl) (8.5g, 72%) as a buff solid m.p. 59-60°.

    [0082] 1H-NMR (CDC13) 60MHz
    δ 7.85-7.55 (m, 1H)
    7.30-6.70 (m, 3H)
    4.25-3.70 (m, 2H)
    3.25-2.80 (m, 2H)

    Description 2



    [0083] 2,3-Dihydro-3-methylindole (D2)

    Following the procedure outlined by G.W. Gribble and J.H. Hoffman, Synthesis 859, 1977, 3-methyl indole (5g) was converted to the title compound (D2) (4.17g, 82%).

    [0084] 1H NMR (CDC13) 60MHz
    δ 7.30-6.30 (m, 4H)
    3.80-2.80 (m, 4H)
    1.30 (d, 3H)

    Description 3


    2,3-Dihydro-5-fluoroindole (D3)



    [0085] 

    Following the procedure outlined in Description 2, 5-fluoroindole (3g) was converted to the title compound (D3) (2.54g, 84%).

    [0086] 1H-NMR (CDCl3) 60MHz
    δ 7.05-6.10 (m, 3H)
    4.10-2.60 (m, 5H)

    Description 4


    2,3-Dihydro-5-chloroindole (D4)



    [0087] 

    Following the procedure outlined in Description 2, 5-chloroindole (0.86g) was converted to the title compound (D4) (0.84g, 97%).

    [0088] 1H-NMR (CDC13) 60MHz
    δ 7.30-6.65 (m, 2H)
    6.60-6.25 (m, 1H)
    4.10-3.25 (m, 3H)
    3.20-2.70 (m, 2H)

    Description 5


    2,3-Dihydro-5-methoxyindole (D5)



    [0089] 

    A solution of 5-methoxyindole (lg) in glacial acetic acid (20ml) was hydrogenated over platinum oxide (0.27g) at room temperature. After absorption of the theoretical amount of hydrogen (153ml), the catalyst was filtered off and the solvent evaporated in vacuo. The residue was basified with saturated potassium carbonate solution and extracted with diethyl ether. The organic phase was dried (Na2SO4), the solvent evaporated in vacuo to give the title compound (D5) (0.43g, 42%).

    [0090] 1H-NMR (CDCl3) 60MHz
    δ 6.85-6.35 (m, 3H)
    3.65 (s, 3H)
    3.60-2.70 (m, 5H) Description 6

    2,3-Dihydro-3-ethylindole (D6)



    [0091] 

    Following the procedure outlined in Description 2, 3-ethylindole (2.3g) (J.T. Fitzpatrick and R.D. Hiser, J. Org. Chem., 22, 1703-4, 1957) was converted to the title compound (D6) (1.3g, 56%).

    [0092] 1H-NMR (CDCl3) 60MHz
    δ 7.20-6.40 (m, 4H)
    3.90-2.90 (m, 4H)
    2.10-0.8 (m, 2H)
    0.9 (t, 3H)

    Description 7


    1-(2,3-Dihydro-3-methyl)indolyl-O-(1-succinimidyl)-carbamate (D7)



    [0093] 



    [0094] N,N-Disuccinimidyl carbonate (8.03g) and 2,3-dihydro-3-methylindole (D2) (4.17g) in dry toluene (150ml) was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in dichloromethane, washed with 5N hydrochloric acid solution (10ml), saturated potassium bicarbonate (10ml) and brine (30ml). The organic phase was dried (Na2SO4). evaporated in vacuo and the residue purified by filtration through a short silica column, eluting with dichloromethane to give the title compound (D7) (6.85g, 80%).

    [0095] 1H-NMR (CDC13) 60MHz
    δ 7.85-6.80 (m, 4H)
    4.60-4.00 (m, 1H)
    3.95-3.10 (m, 2H)
    2.75 (s, 4H)
    1.30 (bd, 3H)

    Description 8


    1-(2,3-Dihydro-5-fluoro)indolyl-0-(1-succinimidyl)-carbamate (D8)



    [0096] 

    Following the procedure outlined in Description 7, reaction of N,N-disuccinimidyl carbonate (4.75g) with 2,3-dihydro-5-fluoroindole (D3) afforded the title compound (D8) (5g, 97%).

    [0097] 1H-NMR (CDC13.) 60MHz
    δ 7.90-7.60 (m, 1H)
    7.30-6.60 (m, 3H)
    4.40-4.00 (m, 2H)
    3.40-2.90 (m, 2H)
    2.85 (s, 4H)

    Description 9


    1-(2,3-Dihydro-5-methoxy)indolyl trichloromethyl carbamate (D9)



    [0098] 

    Following the procedure outlined in Description 1, reaction of 2,3-dihydro-5-methoxyindole (D5) (0.43g) with trichloromethylchloroformate (0.35ml) afforded the title compound (D9) (0.52g, 58%).

    [0099] 1H-NMR (CDC13) 60MHz
    δ 7.88-7.58 (m, 1H)
    6.85-6.48 (m, 2H)
    4.35-3.80 (m, 2H)
    3.70 (s, 3H)
    3.35-2.80 (m, 2H)

    Description 10


    1-(2,3-Dihydro)indolylcarbonyl chloride (D10)



    [0100] 

    To phosgene [110ml (12.5% w/w solution in toluene)] in dry dichloromethane (150ml) at 0° was added dropwise a solution of triethylamine (17ml) and freshly distilled 2,3-dihydroindole (14. 5g) in dry dichloromethane (100ml). The reaction mixture was then stirred at 0° for lh, and then poured into pentane (2.51), wasned with 5N sulphuric acid solution (100ml) and brine (100ml). The organic phase was dried (Na2SO4), the solvent evaporated in vacuo and the residue triturated with 60/80 pet. ether to give the title compound (DlO) (18.37g, 83%).

    Description 11


    1-(2,3-Dihydro-3-ethyl)indolylcarbonyl chloride (Dll)



    [0101] 



    [0102] Following the procedure outlined in Description 10, reaction of 2,3-dihydro-3-ethylindole (D6) (1.25g) with phosgene [7.7ml (12.5% w/w solution in toluene)] afforded the title compound (Dll) (1.6g, 90%).

    Description 12


    1-(2,3-Dihydro-5-nitro)indolyl-trichloromethyl carbamate (D12)



    [0103] 

    Following the procedure outlined in Description 1, reaction of 2, 3-dihydro-5-nitroindole (4.72g) witn trichloromethylchloroformate (3.44ml) afforded the title compound (D12) (5.5g, 59%)

    [0104] 1H-NMR (CDCl3 ) 6OMHz
    δ 8.80-7.10 (m, 3H)
    4.70-3.90 (m, 2H)
    3.50-2.95 (m, 2H)

    Description 13


    1-[1-(2,3-Ditydro-6-nitro)indolylcarbonyl]imidazole (D13)



    [0105] 



    [0106] 2,3-Dihydro-6-nitroindole (3g) and 1,1'-carbonyldiimidazole (2.96g) in dry toluene (75ml) was heated under reflux for 5h. The reaction mixture was cooled and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (100ml) and washed with 5N hydrochloric acid solution (10ml) and water (20ml). The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (D13) (4.7g, 100%).

    Description 14


    1-(2,3-Dihydro-3,3-dimethyl)indolylcarbonyl chloride (D14)



    [0107] 

    Following the procedure outlined in Description 10, reaction of 2,3-dihydro-3,3-dimethylindole (2.7g) with phosgene [16.5ml (12.5% w/w solution in toluene)] afforded the title compound (D14) (3.5g, 91%).

    Example 1


    endo-N-(9-rlethyl-9-azabicyclo[3.3.1]non-3-yl)-2,3-dihydroindole-1-carboxamide (El)



    [0108] 

    To 1-(2,3-dihydro)-indolyltrichloromethyl carbamate (Dl) (3.64g) in dry toluene (100ml) was added endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (2g) in dry toluene (20ml). The reaction mixture was heated under reflux for 24h, then the solvent evaporated in vacuo. The residue was extracted with dichloromethane (200ml) and washed with saturated potassium carbonate solution (2 x 20ml). The organic phase was dried (Na2SO4 ) concentrated and the residue purified by column chromatography on alumina, eluting with CHCl3 to give, after crystallisation from etnyl acetate, the title compound (El) (2g, 52%) m.p. 176-8°.

    [0109] 1H-NMR (CDCl3 ) 270MHz
    δ 7.85 (d, 1H)
    7.25-7.05 (m, 2H)
    6.95-6.85 (m, 1H)
    4.45-4.25 (m, 2H)
    4.00-3.80 (t, 2H)
    3.25-3.05 (m, 4H)
    2.65-2.40 (m, 2H)
    2.50 (s, 3H)
    2.15-1.85 (m, 3H)
    1.65-1.00 (m, 5H)

    Example 2


    endo-N-(8-Nethyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydroindole-l-carboxamide (E2)



    [0110] 

    Following the procedure outlined in Example 1, reaction of 1-(2,3-dihydro)-indolyltrichloromethyl carbamate (Dl) (0.64g) with endo-3-amino-8-methyl-8-azabicyclo-[3.2.1]octane (0.32g) afforded the title compound (E2) m.p. 153-40

    [0111] 1H-NMR (CDC13) 270MHz,
    δ 7.85 (d, 1H)
    7.25-7.10 (m, 2H)
    6.95-6.85 (m, 1H)
    4.95 (bd, 1H)
    4.10 (q, 1H)
    3.90 (t, 2H)
    3.25-3.10 (m, 4H)
    2.25-2.05 (m, 4H)
    2.30 (s, 3H)
    1.90-1.75 (m, 4H)

    Example 3


    endo(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)-2,3-dihydroindole carboxylic acid ester (E3)



    [0112] 

    To 3-tropanol (1.13g) in diglyme (50ml) was added portionwise potassium t-butoxide (0.94g). The reaction mixture was stirred under an atmosphere of N2 at room temperature for lh and then the solvent was evaporated in vacuo. The resultant gum was redissolved in diglyme (50ml) and 1-(2,3-dihydro)indole trichloromethyl carbamate (Dl) (1.5g) was added. The reaction mixture was heated under reflux for 36h, then cooled and evaporated in vacuo. The residue was dissolved in 5N hydrochloric acid solution (10ml) and washed with diethyl ether (30ml). The aqueous phase was basified with potassium carbonate and extracted with dichloromethane (3 x 75ml). The organic phase was dried (Na2SO4), the solvent evaporated in vacuo and the residue purified by column chromatography on alumina eluting with dichloromethane to give, after crystallisation from diethyl ether the title compound (E3) (0.5g, 31%). m.p. 133-40.

    [0113] 1H-NMR (CDC13) 270MHz
    δ 7.85 (bd, 1H)
    7.22-7.12 (m, 2H)
    7.00-6.92 (m, 1H)
    5.05 (t, 1H)
    4.06 (t, 2H)
    3.28-3.08 (m, 4H)
    2.32 (s, 3H)
    2.32-1.75 (m, 8H)

    Example 4


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-methylindole-1-carboxamide hydrochloride (E4)



    [0114] 

    Triethylamine (1.8ml), 1-(2,3-dihydro-3-methyl)indolyl-O-(1-succinimidyl)carbamate (D7) (3.5g) and endo-3-amino-8-azabicyclo[3,2,1]octane (1.8g) were dissolved in dry toluene (100ml) and heated under reflux overnight. The reaction mixture was cooled and the solvent evaporated in vacuo. The residue was extracted with dichloromethane (200ml) and washed with saturated potassium carbonate solution (2 x 20ml). The organic phase was dried (Na2SO4), concentrated and the residue purified by column chromatography on alumina, eluting with chloroform. The product was isolated as the hydrochloride salt (E4) (0.97g, 23%). m.p. 268-70°.

    [0115] 1H-NMR (d6-DMSO) 270MHz
    10.35-10.05 (m, 1H)
    7.75 (d, 1H)
    7.25-7.05 (m, 2H)
    6.95-6.85 (m, lH)
    6.29 (bs, 1H)
    4.15 (t, 1H)
    3.90-3.70 (m, 3H)
    3.65-3.30 (m, 2H)
    2.65 (s, 3H)
    2.50-2.10 (m, 8H)
    1.26 (d, 3H)

    Example 5


    endo-N-(8-Methyl-8-azabiyclo[3.2.1]oct-3-yl)-2,3-dihydro-3,3-dimethylindole-l-carboxamide (E5):



    [0116] 

    Following the procedure outlined in Example 14, reaction of 1-(2,3-dihydro-3,3-dirnethyl)indolylcarbonyl chloride (D14) (1.2g) with endo-3-amino-8-azabicyclo-[3.2.1]octane (0.8g) afforded the title compound (E5) (0.88g, 50%) m.p. 158-90.

    [0117] 1H-NMR CDC13
    7.80 (d, 1H)
    7.25-7.05 (m, 2H)
    7.00-6.90 (m, 1H)
    6.92 (bd, 1H)
    4.08 (q, 1H)
    3.60 (s, 2H)
    3.30-3.15 (m, 2H)
    2.35 (s, 3H)
    2.40-2.10 (m, 4H)
    1.95-1.65 (m, 4H)
    1.35 (s, 6H)

    Example 6


    endo-N-(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)-3-methylindole-1-carboxamide hydrochloride (E6)



    [0118] 

    endo-N-(8-Methyl-8-azabicyclo[.3.2.1]oct-3-yl)-2,3-dihyd ro-3-methylindole-1-carboxamide hydrochloride (E4) (0.5g) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.41g) in dry chloroform (100ml) were heated under reflux for 6h. The reaction mixture was cooled and washed with saturated potassium carbonate solution (20ml). The organic phase was dried (Na2SO4), concentrated and the residue filtered through a short alumina column, eluting with chloroform. The product was isolated as the hydrochloride salt (E6) (0.2g, 40%). m.p. 158-610

    [0119] 1H-NMR (d6-DMSO) 400MHz
    δ 10.50 (bs, 1H)
    8.15 (d, lH)
    7.85 (bs, 1H)
    7.65 (s, 1H)
    7.55 (d, 1H)

    7.30-7.15 (m, 2H) 4.00-3.75 (m, 3H)
    2.65 (bs, 3H)
    2.50-2.05 (m, 1H)

    Example 7


    endo-N-(5-Ethyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydroindole-1-carboxamide (E7)



    [0120] 

    Following the procedure outlined in Example 1, reaction of 1-(2,3-dihydro)indole-trichloromethyl carbamate (D1) (0.91g) with endo-3-amino-8-ethyl-8-azabicyclo-[3.2.1]octane (0.5g) afforded the title compound (E7) (0.24g, 25%) m.p. 140-1°.

    [0121] 1H-NMR (CDCl3) 270MHz
    δ 7.85 (d, 1H)
    7.25-7.10 (m, 2H)
    6.95-6.85 (m, 1H)
    4.95 (bd, 1H)
    4.10 (q, 1H)
    3.90 (t, 2H)
    3.35 (bs, 2H)
    3.15 (t, 2H)
    2.45 (q, 2H)
    2.38-2.20 (m, 2H)
    2.13-2.00 (m, 2H)
    1.95-1.65 (m, 4H)
    1.10 (t, 3H)

    Example 8


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-fluoro-2,3-dihydroindole-1-carboxamide hydrochloride (E8)



    [0122] 

    Following the procedure outlined in Example 4, reaction of 1-(2,3-dihydro-5-fluoro)indolyl-O-(1-succinimidyl)-carbamate (D8) (3.5g) with triethylamine (1.75ml) and endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane (1.76g) afforded the free base, which was converted to the hydrochloride salt (E8) (l.llg, 18%) m.p. 299-3000 (decomposition).

    [0123] 1H-NMR (d6-DMSO) 270MHz
    δ 10.35-10.15 (m, 1H)
    7.80-7.70 (m, 1H)
    7.10-6.85 (m, 2H)
    6.30 (bs, 1H)
    4.05 (t, 2H)
    3.90-3.70 (m, 3H)
    3.10 (t, 2H)
    2.65 (bs, 3H)
    2.50-2.05 (m, 8H)

    Example 9


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-chloroindole-l-carboxamide (E9)



    [0124] 

    To phosgene [3.8ml (12.5% w/w solution in toluene)] in dry dichloromethane (50ml) was added dropwise 2,3-dihydro-5-chloroindole (D4) (0.83g) in CH2C12 (20ml). Triethylamine (0.83ml) was then added and the whole stirred at room temperature for 10 min. endo-3-Amino-8-methyl-8-azabicyclo[3.2.1]octane (0.83g) in dry dichloromethane (10ml) was added and the reaction mixture stirred at room temperature for 2h, then washed with saturated potassium bicarbonate solution (15ml) and brine (20ml). The organic phase was dried (Na2SO4), the solvent evaporated in vacuo and the residue column chromatographed on alumina eluting with chloroform to give, after crystallisation from ethyl acetate, the title compound (E9) (0.36g, 19%) m.p. 149-500.

    [0125] 1H-NMR (CDC13) 400MHz
    6 7.81 (d, 1H)
    7.15-7.05 (m, 2H)
    4.90 (bd, 1H)
    4.08 (q, 1H)
    3.91 (t, 2H)
    3.28-3.10 (m, 4H)
    2.34 (s, 3H)
    2.35-2.08 (m, 4H)
    1.90-1.65 (m, 4H)

    Example 10


    endo-N-(8-riethyl-8-azabicyclo[3.2.1]oct-3-yl)2,3-dihydro-5-methoxyindole-1-carboxamide (E10)



    [0126] 

    Following the procedure outlined in Example 1, reaction of 1-(2,3-dihydro-5-methoxy)indolyl trichloromethyl carbamate (D9) (0.48g) with endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane (0.23g) afforded the title compound (E10) (0.22g, 45%) m.p. 142-50.

    [0127] 1H-NMR (CDC13) 270MHz
    6 7.75 (d, 1H)
    6.80-6.65 (m, 2H)
    4.88 (bd, 1H)
    4.08 (q, 1H)
    3.90 (t, 2H)
    3.78 (s, 3H)
    3.28-3.10 (m, 4H)
    2.32 (s, 3H)
    2.40-2.10 (m, 4H)
    1.90-1.65 (m, 4H)

    Example 11


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)indole-1-carboxamide hydrochloride (Ell)



    [0128] 

    Following the procedure outlined in Example 6, reaction of endo-N-(8-methyl-8-azabieyclo[3.2.1]oct-3-yl)2,3-dihydroindole-l-carboxamide hydrochloride (E2) (0.46g) and 2,3-dichioro-5,6-dicyano-1,4-benzoquinone (0.44g) afforded the title compound (Ell) (0.31g, 68%) m.p. 258-60° (decomposition).

    [0129] 1H-NMR (d6-DMSO) 270MHz
    δ 10.6-10.3 (m, 1H)
    8.15-7.95 (m, 2H)
    7.85 (d, 1H)
    7.65-7.55 (m, 1H)
    7.35-7.10 (m, 2H)
    6.75-6.65 (m, 1H)
    4.05-3.65 (m, 3H)
    2.65 (bs, 3H)
    2.60-2.00 (m, 8H)

    Example 12


    N-(1-Azabicyclo[2.2.2]oct-3-yl)2,3-dihydroindole-1-carboxamide hydrochloride (E12)



    [0130] 

    A mixture of 3-amino-1-azabicyclo[2.2.2]octane (0.5g) and triethylamine (0.7ml) in dry dimethylformamide (30ml) was heated at 50° for lh. The solution was cooled and added dropwise to a solution of l-(2,3-dihydro)indolylcarbonyl chloride (D10) (0.46g) and triethylamine (0.35ml) in dry dimethylformamide (50ml) at 0°. The reaction mixture was stirred at room temperature for 2h, the solvent was then evaporated in vacuo. The residue was dissolved in dichloromethane and washed with 10% sodium hydroxide solution (10ml). The organic phase was dried (Na2SO4), the solvent evaporated in vacuo and the residue was column chromatographed on alumina, eluting with chloroform. The product was isolated as the hydrochloride salt (E12) (0.16g, 21%) m.p. 138-400.

    [0131] 1H-NMR (d6-DMSO) 400MHz
    δ 10.7-10.3 (m, 1H)
    7.82 (d, 1H)
    7.16 (d, 1H)
    7.08 (t, 1H)
    6.86 (t, 1H)
    6.80 (d, lH)
    4.18-4.08 (m, 1H)
    4.06-3.92 (m, 2H)
    2.54 (t, 1H)
    2.46-3.04 (m, 7H)
    2.18-2.06 (m, 2H)
    1.96-1.78 (m, 2H)
    1.76-1.60 (m, lH)

    Example 13


    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,3-dinydroindole-1-carboxylic acid ester (E13)



    [0132] 

    To 1-azabicyclo[2.2.2]octan-3-ol (lg) in dry tetrahydrofuran (75ml) at -78° under an atmosphere of nitrogen, was added dropwise n-butyl lithium [5.2ml (1.6M solution in hexanes)]. The mixture was allowed to warm to room temperature and then stirred for 10 min. The reaction mixture was cooled to -780 and 2,3-dihydroindole (1.43g) in dry tetrahydrofuran (20ml) was added dropwise. The reaction mixture was again allowed to warm to room temperature and stirred overnight. Water was added and the whole evaporated in vacuo, the residue was dissolved in dichloromethane (150ml) and washed with saturated potassium carbonate solution (30ml). The organic phase was dried (Na2SO4), the solvent was evaporated in vacuo and the residue column chromatographed on alumina, eluting with chloroform to give, after crystallisation from ethyl acetate, the title compound (E13) (0.29g, 14%) m.p. 124-50.

    [0133] 1H-NMR (CDC13) 270MHz
    δ 8.00-7.70 (m, 1H)
    7.30-7.10 (m, 2H)
    7.05-6.90 (m, 1H)
    5.05-4.80 (m, 1H)
    4.20-3.95 (m, 2H)
    3.45-3.25 (m, 1H)
    3.25-2.50 (m, 7H)
    2.30-2.05 (m, 1H)
    2.05-1.20 (m, 4H)

    Example 14


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyliridole-1-carboxamide hydrochloride (E14)



    [0134] 

    To l-(2,3-dihydro-3-ethyl)indolylcarbonyl chloride (Dll) (1g) in dry dichloromethane (100ml) was added dropwise a mixture of endo-3-amino-8-azabicyclo[3,2,1] octane (0.7g) and triethylamine (0.7ml) in dry dichloromethane (50ml). The reaction mixture was stirred at room temperature overnight, the solvent was then evaporated in vacuo. The residue aissolved in 5N hydrochloric acid solution (20ml) and washed with diethyl ether (50ml). The aqueous phase was oasified with potassium carbonate and then extracted with dichloromethane (3 x 75ml). The organic phase was dried (Na2SO4), the solvent was evaporated in vacuo and the residue filtered through a short alumina column. The product was isolated as the hydrochloride salt (E14) (1.27g, 76%) m.p. 263-40.

    [0135] 1H-NMR (d6-DMSO) 270MHz
    δ 10.80-10.20 (m, lH)
    7.80 (d, 1H)
    7.25-7.05 (m, 2H)
    6.95-6.80 (m, 1H)
    6.32 (bs, 1H)
    4.10 (t, 1H)
    3.90-3.65 (m, 4H)
    3.55-3.10 (m, 1H)
    2.65 (bs, 3H)
    2.60-2.00 (m, 8H)
    1.90-1.65 (m, 1H)
    1.60-1.40 (m, 1H)
    0.92 (t, 3H)

    Example 15


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-3-ethylindole-l-carboxamide hydrochloride (E15)



    [0136] 

    Following the procedure outlined in Example 6, reaction of endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)2,3-dihydro-3-ethylindole-l-carboxamide hydrochloride (E14) (l.Olg) with 2,3-dicizloro-5,6-dicyano-1,4-benzoquinone (0.8g) afforded the title compound (E15) (0.4g, 40%) m.p. 210-130.

    [0137] 1H-NMR (d6-DMSO) 270MHz
    δ 10.90-10.50 (m, 1H)
    8.15 (d, 1H)
    7.90 (bs, 1H)
    7.68 (s, 1H)
    7.55 (d, 1H)
    7.35-7.10 (m, 2H)
    4.10-3.65 (m, 3H)
    2.90-2.05 (m, 13H)
    1.30 (t, 3H)

    Example 16


    endo-N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-nitroindole-1-carboxamide (E16)



    [0138] 

    Following the procedure outlined in Example 1, reaction of 1-(2,3-dihydro-5-nitro)indolyl trichloromethyl carbamate (D12) (2g) with endo-3-amino-8-azabicyclo-[3.2.1]octane (0.9g) afforded the title compound (E16) (1.25g, 62%) m.p. 176-80.

    [0139] 1H-NMR (CDC13) 270MHz
    δ 8.18-7.95 (m, 3H)
    5.05 (bd, 1H)
    4.15-3.95 (m, 3H)
    3.35-3.15 (m, 4H)
    2.30 (s, 3H)
    2.35-2.10 (m, 4H)
    1.85-1.60 (m, 4H)

    Example 17


    endo-N-(8-Methyl-8-azanicyclo[3.2.1]oct-3-yl)-2,3-dihydro-6-nitroindole-1-carboxamide hydrochloride (E17)



    [0140] 

    Following the procedure outlined in Example 1, reaction of 1-[1-(2,3-dihydro-6-nitro)indolylcarbonyl]imidazole (D13) (4.7g) with endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane (2.55g) afforded the title compound (E17) m.p. 245-7° (decomposition).

    [0141] 1H-NMR (d6-DMSO) 270MHz)
    δ 10.15-9.95 (m, 1H)
    8.55 (d, 1H)
    7.85-7.70 (m, 1H)
    7.45-7.35 (m, 1H)
    6.65-6.55 (m, 1H)
    4.15 (t, 2H)
    3.90-3.70 (m, 1H)
    3.60-3.35 (m, 2H)
    3.30-3.15 (t, 2H)
    2.65 (d, 3H)
    2.45-2.00 (m, 8H)

    Example 18


    N-(1-Azabicyclo[2.2.2]oct-3-yl)2,3-dihydro-3,3-dimethyl indole-l-carboxamide hydrochloride (E18)



    [0142] 

    To a solution of 3-amino-1-azabicyclo[2.2.2]octane dihydrochloride (0.87g) in water (1.5ml) was added dry dimethylformamide (30ml) and triethylamine (2ml). The mixture was stirred at room temperature for 5 min, then a solution of 1-(2,3-dihydro-3,3-dimethyl)indolyl- carbonyl chloride (D14) in dry dimethylformamide (20ml) was added dropwise. The reaction mixture was stirred at room temperature for 18h, the solvent was then evaporated in vacuo. The residue was dissolved in 5N hydrochloric acid solution (25ml) and washed with diethyl ether (50ml). The aqueous phase was basified with potassium carbonate and then extracted with dichloromethane (3 x 75ml). The organic phase was dried (Na2S04), the solvent was evaporated in vacuo and the residue crystallised from ethyl acetate/diethyl ether to give the title compound (E18) m.p. 174-60.

    [0143] 1H-NMR (CDCl3) 270MHz
    11.40 (bs, 1H)
    7.95 (d, 1H)
    7.25-7.05 (m, 2H)
    6.95 (t, 1H)
    6.65 (bd, lH)
    4.60-4.40 (m, 1H)
    4.28 (dd, 1H)
    4.10-3.80 (m, 3H)
    3.55-3.35 (m, 1H)
    3.30-3.00 (m, 3H)
    2.50-2.30 (m, 2H)
    2.25-1.90 (m, 1H)
    1.95-1.60 (m, 2H)
    1.35 (s, 6H)

    Pharmacology


    Antagonism of the von Bezold-Jarisch reflex



    [0144] The compounds were evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:

    Male rats, 250-350g, were anaesthetised with urethane (1.25g/kg intraperitoneally) and blood pressure and heart rate recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A suomaximal dose of 5-HT (usually 6ug/kg) was given repeatedly by the intravenous route and changes in heart rate quantified. Compounds were given intravenously and the concentration required to reduce the 5HT-evoked response to 50% of the control response (ED50) was then determined.



    [0145] The results were as shown in Table 1.




    Claims

    1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

    wherein

    L is NH or O;

    X and Y are independently selected from hydrogen or Cl-4 alkyl, or together are a bond;

    R1 and R2 are independently selected from hydrogen, Cl-6 alkyl, C2-6 alkenyl-Cl-4 alkyl, or together are C2-4 polymethylene;

    R3 and R4 are independently selected from hydrogen, halogen, CF3, C1-6 alkyl, Cl-6 alkoxy, C1-6 alkylthio, Cl-7 acyl, C1-7 acylamino, Cl-6 alkylsulphonylamino, N-(C1-6 alkylsulphonyl)-N-Cl-4 alkylamino, Cl-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-Cl-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl Cl-4 alkyl, phenyl or phenyl C1-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene;

    Z is a group of formula (a), (b) or (c)





    wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and

    R5 or R6 is C1-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl or C2-7 alkenyl-Ci-4 alkyl.


     
    2. A compound according to claim 1 of formula (II):

    wherein Xl and Yl are independently hydrogen, methyl or ethyl, or together are a bond, R11 and R21 are independently hydrogen, methyl or ethyl and the remaining variables are as defined in claim 1.
     
    3. A compound according to claim 2 wherein n is 2.
     
    4. A compound according to claim 2 or 3 wherein R5 is methyl.
     
    5. A compound according to claim 1 of formula (III):

    wherein ql is 1 or 2 and the remaining variables are as defined in claims 1 and 2.
     
    6. A compound according to claim 5 wherein ql is 2.
     
    7. A compound according to any one of claims 1 to 6 wherein one of R3 and R4 is hydrogen and the other is selected from hydrogen, 5-chloro and 5-fluoro.
     
    8. A compound according to any one of claims 1 to 7 wherein L is NH.
     
    9. endo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl) -2,3-dihydroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.l]oct-3-yl) -2,3-dihydroindoie-l-carboxamide,

    endo(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-2,3-dihydroindole carboxylic acid ester,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) -2,3-dihydro-3-methylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabiycio[3.2.1]oct-3-yl) -2,3-dihydro-3,3-dimethylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl) -3-methyl-indole-l-carboxamide,

    endo-N-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl) -2,3-dihydroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) -5-fluoro-2,3-dihydroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-chloroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-methoxyindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-indole-l-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)2,3-dihydroindole-l-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydroindole-l-carboxylic acid ester,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-ethylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-3-ethylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-nitroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-6-nitroindole-l-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)2,3-dihydro-3,3-dimethylindole-1-carboxamide, or the hydrochloride salt of any of the foregoing.


     
    10. A process for the preparation of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (V):

    with a compound of formula (VI):

    wherein
    G is COQ1 where Q1 is a leaving group, or hydrogen; and, when G is COQ1, J is NH2, or OH or a reactive derivative thereof or, when G is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-L-linkage with the compound of formula (V); Z1 is Z as defined or wherein R5/R6 is replaced by a hydrogenolysable protecting group; and the remaining variables are as defined in claim 1; and thereafter optionally converting any R3 and R4 group to another R3 and R4 group respectively, converting Zl, when other than Z, to Z; converting X and Y to other X and Y; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
     
    11. A compound of formula (V) as defined in claim 10, wherein G is COQ1.
     
    12. l-(2,3-Dihydro)-indolyltrichloromethyl carbamate,

    1-(2,3-dihydro-3-methyl)indolyl-O-(1- succinimidyl)carbamate,

    1-(2,3-dihydro-5-fluoro)indolyl-O-(1- succinimidyl)carbamate,

    l-(2,3-dihydro-5-methoxy)indolyl trichloromethyl . carbamate,

    l-(2,3-dihydro)indolylcarbonyl chloride,

    l-(2,3-dihydro-3-ethyl)indolylcarbonyl chloride,

    1-(2,3-dihydro-5-nitro)indolyl-trichloromethyl carbamate,

    1-[1-(2,3-dihydro-6-nitro)indolylcarbonyl]-imidazole, or

    1-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride.


     
    13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.
     
    14. A compound according to any one of claims 1 to 9, for use as an active therapeutic substance.
     
    15. A compound according to any one of claims 1 to 9 for use in the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.
     
    16. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.
     


    Claims

    Claims for the following Contracting State(s) : Spain

    1. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

    wherein

    L is NH or O;

    X and Y are independently selected from hydrogen or Cl-4 alkyl, or together are a bond;

    R1 and R2 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl-C1-4 alkyl, or together are C2-4 polymethylene;

    R3 and R4 are independently selected from hydrogen, halogen, CF3, C1-6 alkyl, Cl-6 alkoxy, Cl-6 alkylthio, Cl-7 acyl, Cl-7 acylamino, Cl-6 alkylsulphonylamino, N-(C1-6 alkylsulphonyl)-N-C1-4 alkylamino, C1-6 alkylsulphinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulphonyl, aminosulphonylamino or N-(aminosulphonyl)-C1-4 alkylamino optionally N-substituted by one or two groups selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, phenyl or phenyl Cl-4 alkyl groups or optionally N-disubstituted by C4-5 polymethylene;

    Z is a group of formula (a), (b) or (c)





    wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and

    R5 or R6 is Cl-7 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-2 alkyl or C2-7 alkenyl-Cl-4 alkyl; which process comprises reacting a compound of formula (V):

    with a compound of formula (VI):

    wherein

    G is COQ1 where Q1 is a leaving group, or hydrogen, and, when G is COQ1, J is NH2, or OH or a reactive derivative thereof or, when G is hydrogen, J is a group containing an activated carbonyl group capable of forming a CO-L-linkage with the compound of formula (V); Z1 is Z as defined or wherein R5/R6 is replaced by a hydrogenolysable protecting group; and the remaining variables are as defined in claim 1; and thereafter optionally converting any R3 and R4 group to another R3 and R4 group respectively, converting Z1, when other than Z, to Z; converting X and Y to other X and Y; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).


     
    2. A process for the preparation of a compound according to claim 1 of formula (II):

    wherein X1 and Y1 are independently hydrogen, methyl or ethyl, or together are a bond, R11 and R21 are independently hydrogen, methyl or ethyl and the remaining variables are as defined in claim 1.
     
    3. A process according to claim 2 wherein n is 2.
     
    4. A process according to claim 2 or 3 wherein R5 is methyl.
     
    5. A process for the preparation of a compound according to claim 1 of formula (III):

    wherein ql is 1 or 2 and the remaining variables are as defined in claims 1 and 2.
     
    6. A process according to claim 5 wherein ql is 2.
     
    7. A process according to any one of claims 1 to 6 wherein one of R3 and R4 is hydrogen and the other is selected from hydrogen, 5-chloro and 5-fluoro.
     
    8. A process according to any one of claims 1 to 7 wherein L is NH.
     
    9. A process according to claim 1 for the preparation of:

    endo-N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl) -2,3-dihydroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) -2,3-dihydroindole-l-carboxamide,

    endo(8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-2,3-dihydroindole carboxylic acid ester,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) -2,3-dihydro-3-methylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabiyclo[3.2.1]oct-3-yl) -2,3-dihydro-3,3-dimethylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl) -3-methyl-indole-l-carboxamide,

    endo-N-(8-ethyl-8-azabicyclo[3.2.1]oct-3-yl) -2,3-dihydroindole-l-carboxamide, endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) -5-fluoro-2,3-dihydroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-chloroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-methoxyindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-indole-1-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)2,3-dihydroindole-l-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydroindole-1-carboxylic acid ester,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-ethylindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-3-ethyl-indole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-5-nitroindole-l-carboxamide,

    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-6-nitroindole-l-carboxamide,

    N-(1-azabicyclo[2.2.2]oct-3-yl)2,3-dihydro-3,3-dimethylindole-l-carboxamide, or the hydrochloride salt of any of the foregoing.


     
    10. Use of a compound prepared by a process according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of migraine, cluster headache, trigeminal neuralgia and/or emesis.
     





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